Research reportNeurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE
Introduction
Understanding the role of apolipoprotein E (apoE) within the central nervous system (CNS) is of great importance because, as recent studies have indicated, the expression of the E4 allele of APOE is a major risk factor for the development of Alzheimer's disease (AD) [25]. ApoE is a 34 kDa protein that is primarily synthesized by astrocytes and microglial/macrophage cells in the nervous system 2, 19. During development the expression of apoE is upregulated [4]and in vitro studies have shown that apoE-containing lipoproteins can promote neuritic outgrowth in an isoform-specific fashion 9, 11, 18. In the mature central nervous system (CNS), apoE plays an important role in transporting esterified cholesterol to the neurons undergoing reinnervation where it is taken up by the low density lipoprotein (LDL) receptor-related protein (LRP) pathway and used as a precursor for the synthesis of new synaptic terminals 20, 21, 22. In fact, in apoE-deficient mice reinnervation of the perforant pathway after lesion is delayed 15, 16, 17. Furthermore, apoE might play a role during aging of the CNS in maintaining the stability of the synapto-dendritic cytoskeleton 15, 16, 17. Supporting this contention, recent studies have shown that in aged apoE-deficient mice there is synaptic and dendritic damage in the neocortex and limbic system, accompanied by disruption of the microtubular cytoskeleton 15, 16, 17. Moreover, apoE-deficient mice display significant cholinergic and memory deficits [6]. Taken together these studies suggest that apoE plays a neurotrophic/neuroprotective function within the CNS and that altered functioning of this molecule could result in neurodegeneration. In this context, the main objectives of the present study were to determine: (1) if the neurodegenerative and cognitive alterations in apoE-deficient mice are reversible by infusion of recombinant apoE into the lateral ventricles, and (2) if these in vivo effects of apoE are isoform specific.
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Colony breeding and characterization
As previously described [17], the homozygous apoE-deficient mice were obtained by cross-breeding heterozygous mutants that were kindly provided by Dr J. Breslow (Rockefeller University, New York, NY). Additional aged homozygous apoE-deficient and wild-type mice (C57BL/6J) were provided by Drs Palinsky and Steinberg (University of California at San Diego, Department of Medicine, La Jolla, CA, USA). A total of 25 apoE-deficient homozygous mice (8 months old) and 21 wild type mice (8 months old)
ApoE-deficient mice are cognitively impaired relative to wildtype controls
During the first five days of pretraining, when the platform was visible the two groups did not significantly differ in the distance swum to reach the platform [Near Vis F(1,13)<1; Far Vis F(1,13)=3.32, n.s) (Fig. 1A). However, on the following 6 days of training when the platform was submerged (Invis), the apoE-deficient mice had a longer mean swim distance when compared to wildtype controls [F(1,13)=14.02, P<0.003] (Fig. 1A). This learning impairment was not due to motor or visual disability,
Discussion
The present study showed that infusion of apoE into the lateral ventricles of apoE-deficient mice corrects the synapto-dendritic pathology and indicates that these alterations are reversible. This in vivo neurotrophic effect is consistent with previous in vitro studies that have shown the apoE-dependent neuritic outgrowth in dorsal root ganglion neurons [9]. These effects in tissue culture were blocked by addition of anti-apoE or by reductive methylation of apoE [9]. While, in in vitro studies
Acknowledgements
This paper was supported by NIH grants AG05131, AG10689 and with funding from the Alzheimers Disease Association and Ruth K. Broad Foundation. This work was also partially supported by NIH grant RR04050.
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